Oncogenic activation of ERG: A predominant mechanism in prostate cancer

Abstract

Prevalent gene fusions involving regulatory sequences of the androgen receptor (AR) regulated genes (primarily TMPRSS2) and protein coding sequences of nuclear transcription factors of the ETS gene family (predominantly ERG) result in unscheduled androgen dependent ERG expression in prostate cancer (CaP).Cumulative data from a large number of studies in the past six years accentuate ERG alterations in more than half of all CaP patients in Western countries. Studies underscore that ERG functions are involved in the biology of CaP. ERG expression in normal context is selective to endothelial cells, specific hematopoetic cells and pre-cartilage cells. Normal functions of ERG are highlighted in hematopoetic stem cells. Emerging data continues to unravel molecular and cellular mechanisms by which ERG may contribute to CaP. Herein, we focus on biological and clinical aspects of ERG oncogenic alterations, potential of ERG-based stratification of CaP and the possibilities of targeting the ERG network in developing new therapeutic strategies for the disease.

Keywords: ERG; TMPRSS2-ERG; androgen receptor; oncoprotein; patient stratification; prostate cancer.

Figure 1

Genomic structure and transcripts of human ERG gene. (a) Genomic structure depicting ERG Exons (blue boxes) numbered from 1-17.[53] (b) Structure of expressed ERG transcripts.[53] (c) Prostate cancer specific TMPRSS2-ERG fusion transcripts containing protein-protein interaction domain (pointed/SAM) and DNA binding (ETS) domain (Type I).[81] (d). TMPRSS2-ERG fusion Type II transcripts containing only pointed/SAM without ETS domain.[81] Note: In prostate cancer, the original ERG exon 8[53] is numbered as 4.[407887]

Figure 2

ERG regulated prostate cancer pathways.ERG regulates the expression of target genes associated with cancer initiation and progression pathways such as DNA damage, inflammation,epigenetic control,regulation of differentiation, EMT, cell proliferation and cell invasion. (Red: upregulated;Green:down regulated;Yellow: protein-protein interactions)

Figure 3

ERG-dependent Clonal Selection of Prostate Tumors. Model describing the ERG-dependent clonal selection of prostate tumors from prostatic intraepithelial neoplasia (PIN) to prostate cancer. Other precursor lesions which may not progress through the PIN morphological stage are not represented by this model. Normal prostate epithelial cells are marked by green color

Figure 4

Detection of PIN and prostatic adenocarcinoma by the combination of ERG, AMACR, p63 and CK5 markers in immunohistochemistry.Tumor cells are positive for nuclear ERG (brown) and cytoplasmic AMACR (green), whereas, absence of p63 (purple) and CK5 (purple) indicate the lack of basal cell layer. By contrast, in normal prostatic glands prominent staining with p63 and CK5 distinctively demarcate intact basal cell layer.In PIN disrupted basal cell layer and prominent ERG and AMACR staining is apparent (×400). (Image: Courtesy of Dr. David Tacha, Biocare Medical Inc, Concord, CA, USA)